Alcohol increases treatment failure for Helicobacter pylori eradication in Asian populations

Background and Aim Whether alcohol intake is associated with Helicobacter pylori (H. pylori) eradication failure remains controversial, and this meta-analysis was aimed at investigating the effect of alcohol on the risk of H. pylori eradication failure. Methods Relevant studies were systematically screened for and retrieved from PubMed and Web of Science (updated to January 2022), and relevant references were manually reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup, publication bias, and sensitivity analyses were also conducted. Results A total of 40 studies were included in the meta-analysis. No significant association was found between alcohol consumption and the risk of H. pylori eradication failure (OR = 1.09, 95% CI, 0.94–1.26). However, in subgroup analyses stratified by region, a positive association was found in Asian patients (OR = 1.23, 95% CI, 1.03–1.47). In Asian patients, alcohol consumption was associated with the risk of H. pylori eradication failure when the duration of therapy was > 7 days (OR = 1.17, 95% CI, 1.10–1.25), when the treatment regimen included nitroimidazoles (OR = 1.16, 95% CI, 1.09–1.24), and when patients were treated with bismuth-containing quadruple therapy (OR = 1.17, 95% CI, 1.10–1.25). Alcohol intake > 40 g/day was associated with H. pylori eradication failure (OR = 3.17, 95% CI, 1.56–6.41). Moreover, in Asian patients who were administered a vonoprazan (VPZ)-based therapy regimen, alcohol consumption had no effect on H. pylori eradication rates (OR = 1.73, 95% CI, 0.98–3.05). Conclusion Our meta-analysis clearly showed that a higher daily alcohol intake was associated with a higher risk of H. pylori eradication failure in Asian populations. Moreover, a VPZ-based treatment regimen can prevent this effect.


Introduction
Helicobacter pylori (H.pylori) infection is among the most prevalent infections in the world and affects approximately half of the population in Asia [1].H. pylori can cause chronic gastritis, peptic ulcers, stomach cancer, and other digestive system diseases.Treatment of H. pylori infection can effectively control the occurrence and development of these diseases [2,3].The ideal regimen for treating H. pylori infection should return eradication rates of more than 90%-95% and 80% in per-protocol and intention-to-treat analyses, respectively, and should be well tolerated with few adverse effects (< 5%) [4].However, sequential, concomitant, and bismuth-containing therapies used for H. pylori infection in recent years have not achieved satisfactory eradication rates [5].As the chances of successful eradication decrease with increasing number of follow-up eradication attempts, factors leading to eradication failure should be identified and avoided to the extent possible [6].
Some studies have examined the influence of several factors on H. pylori eradication.The most common factors showing significant correlation with H. pylori eradication were antibiotic resistance [7,8], smoking [9], cytochrome P450 (CYP) 2C19 genotype [10], body mass index (BMI) [3,11], and poor treatment adherence [1,12].However, the effect of alcohol on H. pylori eradication has been less explored with controversial findings.Alcohol consumption was reported to significantly lower the H. pylori eradication rate [11,12], suggesting its role in the increased risk of H. pylori eradication failure.Conversely, some studies have reported no association between alcohol consumption and the risk of H. pylori eradication failure [13][14][15].Meanwhile, vonoprazan (VPZ), a novel potassium-competitive acid blocker (P-CAB), has been recently approved in Japan for H. pylori eradication [16].Studies have shown that alcohol consumption does not affect the eradication rate of VPZbased treatment regimens [2,16,17].Therefore, a metaanalysis was conducted to clarify these discrepancies and investigate the association between alcohol consumption and the risk of H. pylori eradication failure.

Methods
This meta-analysis was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines [18].The research problem was based on the PICO model: P [population]: Studies that recruited patients with H. pylori infection as participants; I [intervention or exposure]: alcohol consumption; C [comparison agent]: comparison between the alcohol group and the control group; and O [result]: H. pylori eradication.

Search strategy
A literature search was conducted on PubMed and Web of Science for all relevant literature published before January 2022 using the keywords (Helicobacter pylori eradication OR H. pylori eradication) AND (alcohol OR drinking).Some relevant studies were included on the basis of a manual review of references as well.

Inclusion criteria
In our meta-analysis, we included (1) studies exploring the effect of different levels of alcohol exposure (high vs. low; any vs. none) on H. pylori eradication; (2) studies with data for odds ratios (ORs) available or those in which the number of eradication cases could be obtained according to the drinking category; (3) studies published in English; and (4) first-line or second-line treatment studies for H. pylori eradication.Notably, if there were multiple studies of the same study population, the study with the largest sample size was included.

Exclusion criteria
We excluded (1) case reports, meeting abstracts, and commentaries; (2) studies with incomplete data; and (3) studies that were duplication or continuation of previous studies.

Data extraction
Two researchers (J.Y. and Y-M.L.) separately extracted information from all eligible articles and cross-checked each other's findings.Any inconsistencies in results were resolved by a third senior investigator (X-Y.W.) until a consensus was reached.The following information was extracted for each study: first author, year of publication, country, study design, proportion of patients with peptic ulcers, number of participants, eradication regimens, treatment duration, method for assessing H. pylori eradication, interval for assessing H. pylori eradication after the therapy, and alcohol consumption.In addition, the quality of each included study was assessed independently by the two researchers using the Newcastle-Ottawa Scale (NOS) on the basis of three broad domains of selection, comparability, and exposure/outcome.Each study was scored on a scale of 0 to 9.

Statistical analysis
The association between alcohol consumption and the risk of H. pylori eradication failure was calculated using ORs and 95% confidence intervals (CIs).The reported OR and 95% CI were used when available and calculated when not available.Heterogeneity between studies was assessed by the Q test and I 2 test.I 2 ≤ 50% and P > 0.05 suggested no statistical heterogeneity, and in this case, the fixed-effects model was selected for data analysis; otherwise, the random-effects model was applied.Subgroup analysis was performed to explore the source of heterogeneity.Sensitivity analysis was performed to ensure the stability of meta-analysis results.Funnel plots were used for visual evaluation of publication bias; Egger's and Begg's tests were used for statistical assessment of publication bias.A P value of < 0.05 was considered statistically significant.All statistical analyses were performed using Stata software version 15.1 (Stata Corp LLC 4905 Lake Way Drive, College Station, TX 77845 USA).

Study identification and selection
Figure 1 shows the details of literature retrieval.First, using the abovementioned keywords, 244 and 208 studies were obtained from PubMed and Web of Science, respectively.From among these studies, 114 studies were excluded because of duplication.Then, the titles and abstracts of the remaining 338 publications were reviewed, and 286 studies that did not meet the inclusion criteria were excluded.Then, the full text of the remaining 52 studies was evaluated, and 9 studies were included through manual retrieval of their references.From among these 61 studies, 21 studies were excluded because 11 studies did not contain sufficient data and 10 studies were not published in English.Finally, 40 studies were included in the final analysis.

Association between alcohol consumption and the risk of H. pylori eradication failure
Finally, 40 studies reporting the association between alcohol consumption and H. pylori eradication were analyzed.Owing to the significant heterogeneity among these studies (I 2 = 47.9%,P-heterogeneity < 0.001), a random-effects model was applied.The risk of H. pylori eradication failure was not higher in drinkers than in non-drinkers (OR = 1.09, 95% CI, 0.94-1.26)(Fig. 2).To assess the effect of each individual study on the pooled effect size, sensitivity tests were performed by excluding one study at a time.Withdrawal of any study did not significantly alter the results.The pooled OR ranged from 0.94 to 1.26, confirming the robustness of the results.Neither visual assessment using the funnel plot (Fig. 3a) nor statistical assessment with Begg's test (P = 0.401) or Egger's test (P = 0.805) revealed any publication bias.

Association between alcohol consumption and the risk of H. pylori eradication failure in Asia
Herein, 24 Asian studies reported on the effect of alcohol consumption on H. pylori eradication.There was significant heterogeneity among these studies (I 2 = 41.5%,P-heterogeneity = 0.012), and a randomeffects model was applied.The analysis results revealed alcohol as a risk factor for H. pylori eradication failure (OR = 1.23, 95% CI, 1.03-1.47)(Fig. 2).Next, sensitivity analysis was performed, and the pooled OR ranged from 1.03 to 1.47, confirming the robustness of the results.The funnel plot (Fig. 3b) was roughly symmetrical, and there was no publication bias on Begg's test (P = 0.489) or Egger's test (P = 0.455).

Subgroup analysis
The origin of heterogeneity was explored by subgroup analysis (Table 2).No significant differences were observed between the prospective studies (OR = 1.13, 95% CI, 0.92-1.38)and retrospective studies (OR = 1.05, 95% CI, 0.83-1.32),all of which indicated that alcohol consumption did not increase the risk of H. pylori eradication failure.When stratified by treatment options, a higher risk of eradication failure was not observed among drinkers undergoing first-line treatment (OR = 1.09, 95% CI, 0.94-1.26)or second-line treatment (OR = 1.25, 95% CI, 0.54-2.93).No significant differences were found between studies having all patients with peptic ulcer (OR = 0.83, 95% CI, Fig. 2 A forest plot of the association between alcohol and H. pylori eradication.Subgroup analysis was based on the region 0.65-1.07)and those having a proportion of patients with peptic ulcer (OR = 1.19, 95% CI, 0.93-1.51),all of which indicated that alcohol consumption did not increase the risk of H. pylori eradication failure.Urea breath test (OR = 0.98, 95% CI, 0.82-1.16)and other methods (OR = 0.75, 95% CI, 0.51-1.09)used to evaluate H. pylori eradication were not associated with a higher risk of H. pylori eradication failure among drinkers.Moreover, in Asian patients (Table 3), a treatment duration of > 7 days was associated with higher risk of H. pylori eradication failure (OR = 1.17, 95% CI, 1.10-1.25).Alcohol consumption was found to increase the risk of H. pylori eradication failure when the treatment regimen did not include clarithromycin (OR = 1.18, 95% CI, 1.10-1.26)or when the treatment regimen included nitroimidazoles (OR = 1.16, 95% CI, 1.09-1.24).Notably, alcohol consumption also decreased the eradication rate when bismuth-containing quadruple therapy (OR = 1.17, 95% CI, 1.10-1.25)was used to treat H. pylori infection in Asian patients; however, the H. pylori eradication efficacy of the VPZ-based therapy regimen (OR = 1.73, 95% CI, 0.98-3.05)remained unaffected by alcohol consumption.In addition, seven of the Asian studies provided information on the amount of alcohol intake.In these studies, increase in alcohol intake (> 40 g/day) was associated with a higher risk of H. pylori eradication failure (OR = 3.17, 95% CI, 1.56-6.41).

Main findings
Our meta-analysis included 40 studies and assessed the potential association between alcohol consumption and the risk of H. pylori eradication failure.The overall pooled OR of drinkers versus non-drinkers was 1.09 (95% CI: 0.94-1.26),suggesting that alcohol consumption was not associated with and did not exacerbate the risk of H. pylori eradication failure.Stratified by the study region, our meta-analysis showed that increased alcohol consumption was associated with increased risk of H. pylori eradication failure in Asian studies.Compared to controls, individuals with alcohol consumption of over 40 g/ day were more than three times likely to encounter H. pylori eradication failure.The association between alcohol consumption and the risk of H. pylori eradication failure is supported by several biological mechanisms.First, alcohol consumption activates gastric acid secretion, leading to a decrease in stomach pH, which promotes the breakdown of antibiotics and reduces their effectiveness [41].In addition, ethanol can reportedly significantly affect the absorption rate of amoxicillin [47].Second, alcohol has a strong induction effect on the liver enzyme CYP2C19 [48].Meanwhile, for the CYP2C19 genotype, H. pylori eradication rates were reported to be lower in the rapid and intermediate metabolizer groups of proton pump inhibitors (PPIs) than in poor metabolizer groups [10].Therefore, alcohol may affect the eradication rate by inducing CYP2C19.Moreover, alcohol can also alter the gastric microenvironment, thus affecting the stability of antibiotics and leading to a decrease in the eradication rate [44].
The discrepancy between the results of Asian and non-Asian studies may be explained by potential differences in their regional populations, such as genetic and physical differences.There are two major aldehyde dehydrogenase (ALDH) isoenzymes in the liver: cytoplasmic ALDH1 and mitochondrial ALDH2.The primary pathway by which ethanol is metabolized involves its degradation by alcohol dehydrogenase into acetaldehyde (an intermediate metabolite), which is then acted upon by ALDH and converted into acetic acid [49].Previous studies have reported a widespread prevalence of ALDH deficiency in Oriental populations [50], and thus, it can be interpreted that Asians metabolize ethanol less efficiently than non-Asians.In addition, for the same BMI, Asians have a higher body fat percentage than Caucasians [51], and alcohol is not easily absorbed by adipose tissues because of its low fat solubility [52].These factors also contribute to higher plasma alcohol concentrations in Asian populations than in non-Asian populations.These results suggest that alcohol consumption impacts Asian populations more strongly and therefore influences H. pylori eradication to a greater extent.
In Japan, the standard treatment for H. pylori eradication is a seven-day triple therapy, namely PPI or P-CAB combined with amoxicillin, clarithromycin, or metronidazole [53].As a novel P-CAB, VPZ has been approved for H. pylori eradication in recent years [16].Our findings showed that alcohol consumption did not detrimentally affect the efficacy of the VPZ-based therapy regimen, and although the reasons for this remain unknown, we can speculate that the strong inhibition of gastric acid by VPZ conceals the effect of alcohol on the H. pylori eradication rate [2].Therefore, to further explore this phenomenon, prospective studies on the efficacy and safety of the VPZ-based therapy regimen in a larger population are warranted, particularly in other regions besides Japan.Future research should also focus

Strengths and limitations of analysis
The present study has several limitations.First, several confounding factors differed among studies, such as BMI, race, study design, and treatment regimen; this may have influenced the results of our study.Second, studies have shown that the existence of the dose-response gradient can improve the quality of evidence [54].Since only seven Asian studies provided information on alcohol intake, the questionnaire was not an ideal source of data in most Asian studies included herein.Therefore, we could only incorporate these seven studies into the doseresponse analysis of alcohol consumption and H. pylori eradication.Further studies are needed to examine the relationship between different alcohol intake doses and the corresponding risk of H. pylori eradication failure.Third, we did not analyze the effect of the type of alcohol consumed on H. pylori eradication rates, and since different types of alcohol have different potentially relevant properties in this regard, for example, some studies have shown that wine has antibacterial properties, this perspective deserves further exploration [55,56].Finally, most of the included studies did not test for antibiotic resistance in their trials, which may have influenced the H. pylori eradication rate.Nonetheless, despite these limitations, to our knowledge, this is the first meta-analysis to explore the relationship between alcohol consumption and the risk of H. pylori eradication failure.In addition, VPZ is a novel P-CAB that has been recently approved in Japan for H. pylori eradication.We included relevant literature to provide the first comprehensive analysis of whether alcohol consumption has an effect on H. pylori eradication in individuals undergoing the VPZ-based therapy.Further large-scale, multicenter prospective studies are warranted to verify our results.

Conclusion
In summary, our meta-analysis suggests that alcohol consumption increases the H. pylori eradication failure rate in Asian populations.Alcohol intake of > 40 g/day was associated with H. pylori eradication failure.It should also be noted that alcohol consumption may not negatively affect H. pylori eradication rates when the VPZbased therapy regimen is being used to treat H. pylori infection in Asian populations.Therefore, we suggest that for Asian populations, drinkers should abstain from alcohol to improve the H. pylori eradication rate; furthermore, in patients having difficulty in abstaining from alcohol, the VPZ-based therapy regimen can be adopted to avoid the influence of alcohol on treatment efficacy.

Fig. 1
Fig. 1 Flow chart of study selection

Fig. 3
Fig. 3 Funnel plots of publication bias (a: All studies included, b: Asian studies).Each round dot represents one study; Begg's test or Egger's test also showed no evidence of publication bias in both A and B subfigures

Table 1
Characteristics of included studies

Table 3
Subgroup analyses between alcohol consumption and the risk of H. pylori eradication failure in AsiaAbbreviations: HP Helicobacter pylori, VPZ Vonoprazan